The transmissible neurodegenerative encephalopathies (called prion diseases) in mammals and humans, as well as age-related pathologies such as Alzheimer's syndrome, are associated with a nucleated polymerization" process leading to the formation of protein aggregates. Prion diseases and Alzheimer's syndrome are fatal and incurable. The "protein only" model of prion diseases suggests that abnormal prion protein may serve as an infectious agent by "seeding" formation of the new prions. Recent finding of prion-like proteins in the yeast Saccharomyces cerevisiae suggests a wide distribution and possible biological importance of prion phenomena. From the geneticist' s point of view, the "protein only" model of prion phenomena suggests that, in addition to the information which is coded by the sequence, some protein and/or multiprotein structures contain additional information which is "coded" in the structure itself. Highly ordered cellular structures such as cytoskeletal formations, are the most likely candidates for the systems of "structural" coding. The proposed project is designed to test a hypothesis, which states that the appearance of prion aggregates results from an abortive form of the structure-forming process, normally leading to assembly of the ordered intracellular or extracellular multiprotein complexes. The yeast prion- forming translational release factor Sup35p (eRF3) will be used as an experimental model. Roles of the chaperone helpers and cytoskeleton- associated proteins in formation and propagation of the Sup35pPSI prion, and in the cytoskeletal assembly will be compared by using genetic and biochemical approaches. Protein-protein interactions, which involve the prion-forming domain of the Sup35p, will be characterized. Results obtained will shed light on the mechanisms, integrating the potential prion-forming processes into normal cellular physiology, and may eventually lead to the development of new cures for prion diseases and related disorders.